Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Peter Ebert; Peter A. Audano; Qihui Zhu; Bernardo Rodriguez-Martin; David Porubsky; Marc Jan Bonder; Arvis Sulovari; Jana Ebler; Weichen Zhou; Rebecca Serra Mari; Feyza Yilmaz; Xuefang Zhao; Ping Hsun Hsieh; Joyce Lee; Sushant Kumar; Jiadong Lin; Tobias Rausch; Yu Chen; Jingwen Ren; Martin Santamarina; Wolfram Höps; Hufsah Ashraf; Nelson T. Chuang; Xiaofei Yang; Katherine M. Munson; Alexandra P. Lewis; Susan Fairley; Luke J. Tallon; Wayne E. Clarke; Anna O. Basile; Marta Byrska-Bishop; André Corvelo; Uday S. Evani; Tsung Yu Lu; Mark J.P. Chaisson; Junjie Chen; Chong Li; Harrison Brand; Aaron M. Wenger; Maryam Ghareghani; William T. Harvey; Benjamin Raeder; Patrick Hasenfeld; Allison A. Regier; Haley J. Abel; Ira M. Hall; Paul Flicek; Oliver Stegle; Mark B. Gerstein; Jose M.C. Tubio; Zepeng Mu; Yang I. Li; Xinghua Shi; Alex R. Hastie; Kai Ye; Zechen Chong; Ashley D. Sanders; Michael C. Zody; Michael E. Talkowski; Ryan E. Mills; Scott E. Devine; Charles Lee; Jan O. Korbel; Tobias Marschall; Evan E. Eichler

doi:10.1126/science.abf7117

Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Peter Ebert, Peter A. Audano, Qihui Zhu, Bernardo Rodriguez-Martin, David Porubsky, Marc Jan Bonder, Arvis Sulovari, Jana Ebler, Weichen Zhou, Rebecca Serra Mari, Feyza Yilmaz, Xuefang Zhao, Ping Hsun Hsieh, Joyce Lee, Sushant Kumar, Jiadong Lin, Tobias Rausch, Yu Chen, Jingwen Ren, Martin SantamarinaWolfram Höps, Hufsah Ashraf, Nelson T. Chuang, Xiaofei Yang, Katherine M. Munson, Alexandra P. Lewis, Susan Fairley, Luke J. Tallon, Wayne E. Clarke, Anna O. Basile, Marta Byrska-Bishop, André Corvelo, Uday S. Evani, Tsung Yu Lu, Mark J.P. Chaisson, Junjie Chen, Chong Li, Harrison Brand, Aaron M. Wenger, Maryam Ghareghani, William T. Harvey, Benjamin Raeder, Patrick Hasenfeld, Allison A. Regier, Haley J. Abel, Ira M. Hall, Paul Flicek, Oliver Stegle, Mark B. Gerstein, Jose M.C. Tubio, Zepeng Mu, Yang I. Li, Xinghua Shi, Alex R. Hastie, Kai Ye, Zechen Chong, Ashley D. Sanders, Michael C. Zody, Michael E. Talkowski, Ryan E. Mills, Scott E. Devine, Charles Lee, Jan O. Korbel, Tobias Marschall, Evan E. Eichler

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Abstract

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

Original language	English (US)
Article number	48
Journal	Science
Volume	372
Issue number	6537
DOIs	https://doi.org/10.1126/science.abf7117
State	Published - Apr 2 2021
Externally published	Yes

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© 2021 American Association for the Advancement of Science. All rights reserved.

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Ebert, P., Audano, P. A., Zhu, Q., Rodriguez-Martin, B., Porubsky, D., Bonder, M. J., Sulovari, A., Ebler, J., Zhou, W., Mari, R. S., Yilmaz, F., Zhao, X., Hsieh, P. H., Lee, J., Kumar, S., Lin, J., Rausch, T., Chen, Y., Ren, J., ... Eichler, E. E. (2021). Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science, 372(6537), Article 48. https://doi.org/10.1126/science.abf7117

Ebert, P, Audano, PA, Zhu, Q, Rodriguez-Martin, B, Porubsky, D, Bonder, MJ, Sulovari, A, Ebler, J, Zhou, W, Mari, RS, Yilmaz, F, Zhao, X, Hsieh, PH, Lee, J, Kumar, S, Lin, J, Rausch, T, Chen, Y, Ren, J, Santamarina, M, Höps, W, Ashraf, H, Chuang, NT, Yang, X, Munson, KM, Lewis, AP, Fairley, S, Tallon, LJ, Clarke, WE, Basile, AO, Byrska-Bishop, M, Corvelo, A, Evani, US, Lu, TY, Chaisson, MJP, Chen, J, Li, C, Brand, H, Wenger, AM, Ghareghani, M, Harvey, WT, Raeder, B, Hasenfeld, P, Regier, AA, Abel, HJ, Hall, IM, Flicek, P, Stegle, O, Gerstein, MB, Tubio, JMC, Mu, Z, Li, YI, Shi, X, Hastie, AR, Ye, K, Chong, Z, Sanders, AD, Zody, MC, Talkowski, ME, Mills, RE, Devine, SE, Lee, C, Korbel, JO, Marschall, T & Eichler, EE 2021, 'Haplotype-resolved diverse human genomes and integrated analysis of structural variation', Science, vol. 372, no. 6537, 48. https://doi.org/10.1126/science.abf7117

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title = "Haplotype-resolved diverse human genomes and integrated analysis of structural variation",

abstract = "Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.",

author = "Peter Ebert and Audano, {Peter A.} and Qihui Zhu and Bernardo Rodriguez-Martin and David Porubsky and Bonder, {Marc Jan} and Arvis Sulovari and Jana Ebler and Weichen Zhou and Mari, {Rebecca Serra} and Feyza Yilmaz and Xuefang Zhao and Hsieh, {Ping Hsun} and Joyce Lee and Sushant Kumar and Jiadong Lin and Tobias Rausch and Yu Chen and Jingwen Ren and Martin Santamarina and Wolfram H{\"o}ps and Hufsah Ashraf and Chuang, {Nelson T.} and Xiaofei Yang and Munson, {Katherine M.} and Lewis, {Alexandra P.} and Susan Fairley and Tallon, {Luke J.} and Clarke, {Wayne E.} and Basile, {Anna O.} and Marta Byrska-Bishop and Andr{\'e} Corvelo and Evani, {Uday S.} and Lu, {Tsung Yu} and Chaisson, {Mark J.P.} and Junjie Chen and Chong Li and Harrison Brand and Wenger, {Aaron M.} and Maryam Ghareghani and Harvey, {William T.} and Benjamin Raeder and Patrick Hasenfeld and Regier, {Allison A.} and Abel, {Haley J.} and Hall, {Ira M.} and Paul Flicek and Oliver Stegle and Gerstein, {Mark B.} and Tubio, {Jose M.C.} and Zepeng Mu and Li, {Yang I.} and Xinghua Shi and Hastie, {Alex R.} and Kai Ye and Zechen Chong and Sanders, {Ashley D.} and Zody, {Michael C.} and Talkowski, {Michael E.} and Mills, {Ryan E.} and Devine, {Scott E.} and Charles Lee and Korbel, {Jan O.} and Tobias Marschall and Eichler, {Evan E.}",

year = "2021",

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doi = "10.1126/science.abf7117",

language = "English (US)",

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AU - Ebert, Peter

AU - Audano, Peter A.

AU - Zhu, Qihui

AU - Rodriguez-Martin, Bernardo

AU - Porubsky, David

AU - Bonder, Marc Jan

AU - Sulovari, Arvis

AU - Ebler, Jana

AU - Zhou, Weichen

AU - Mari, Rebecca Serra

AU - Yilmaz, Feyza

AU - Zhao, Xuefang

AU - Hsieh, Ping Hsun

AU - Lee, Joyce

AU - Kumar, Sushant

AU - Lin, Jiadong

AU - Rausch, Tobias

AU - Chen, Yu

AU - Ren, Jingwen

AU - Santamarina, Martin

AU - Höps, Wolfram

AU - Ashraf, Hufsah

AU - Chuang, Nelson T.

AU - Yang, Xiaofei

AU - Munson, Katherine M.

AU - Lewis, Alexandra P.

AU - Fairley, Susan

AU - Tallon, Luke J.

AU - Clarke, Wayne E.

AU - Basile, Anna O.

AU - Byrska-Bishop, Marta

AU - Corvelo, André

AU - Evani, Uday S.

AU - Lu, Tsung Yu

AU - Chaisson, Mark J.P.

AU - Chen, Junjie

AU - Li, Chong

AU - Brand, Harrison

AU - Wenger, Aaron M.

AU - Ghareghani, Maryam

AU - Harvey, William T.

AU - Raeder, Benjamin

AU - Hasenfeld, Patrick

AU - Regier, Allison A.

AU - Abel, Haley J.

AU - Hall, Ira M.

AU - Flicek, Paul

AU - Stegle, Oliver

AU - Gerstein, Mark B.

AU - Tubio, Jose M.C.

AU - Mu, Zepeng

AU - Li, Yang I.

AU - Shi, Xinghua

AU - Hastie, Alex R.

AU - Ye, Kai

AU - Chong, Zechen

AU - Sanders, Ashley D.

AU - Zody, Michael C.

AU - Talkowski, Michael E.

AU - Mills, Ryan E.

AU - Devine, Scott E.

AU - Lee, Charles

AU - Korbel, Jan O.

AU - Marschall, Tobias

AU - Eichler, Evan E.

PY - 2021/4/2

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AB - Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

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Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Abstract

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